Pim1-GPX4介导的铁死亡通路在胰腺癌及其吉西他滨耐药中的作用和机制研究

对吉西他滨耐药是影响胰腺癌化疗疗效的主要原因之一，如何逆转或改善耐药是亟待解决的关键问题。近期研究发现，GPX4依赖性铁死亡参与了胰腺癌细胞对吉西他滨耐药，但其具体机制不明。我们前期研究发现，Pim1敲降可诱导胰腺癌细胞铁死亡并降低GPX4的蛋白水平，同时，Pim1敲降还能抑制GPX4的上游调控蛋白SLC7A11和Nrf2。此外，Pim1与GPX4存在直接相互作用，生信分析提示GPX4可被Pim1磷酸化修饰。据此我们推测：Pim1可通过Nrf2-SLC7A11通路和/或磷酸化修饰的途径调控GPX4，抵抗胰腺癌细胞铁死亡，而抑制Pim1可逆转或改善吉西他滨耐药。本项目拟通过过表达及敲降、质谱和体外激酶实验等技术对Pim1调控GPX4的具体机制展开深入研究；并结合裸鼠模型，明确抑制Pim1诱导的铁死亡在吉西他滨耐药中的作用。该项目将加深对胰腺癌耐药机制的理解，并为胰腺癌的治疗提供新的思路。

Resistance to gemcitabine is one of the main factors affecting the efficacy of chemotherapy for pancreatic cancer. How to reverse or improve resistance is a critical problem to be solved urgently. Recent studies have shown that GPX4-dependent ferroptosis is involved in the resistance to gemcitabine, but the mechanism is unclear. Our prior study found that Pim1 knockdown induced ferroptosis and reduced GPX4 protein level in pancreatic cancer cells. Furthermore, Pim1 knockdown inhibited the upstream regulators of GPX4, such as SLC7A11 and NrfF2. In addition, Pim1 directly interacted with GPX4, and bioinformatics analysis implied that GPX4 could be phosphorylated by Pim1. We suppose that Pim1 regulates GPX4 through the Nrf2-SLC7A11 pathway and/or phosphorylation to prevent pancreatic cancer cells from ferroptosis, and Pim1 inhibition could reverse or improve gemcitabine resistance. In this project, we will conduct further studies on the specific mechanisms of GPX4 regulated by Pim1 using overexpression and knockdown, mass spectrometry and in vitro kinase assay, et al.. The relationship between Pim1 inhibition-induced ferroptosis and gemcitabine resistance in pancreatic cancer was clarified using nude mouse model. This project will deepen the understanding of the mechanisms of pancreatic cancer resistance and provide new strategies for pancreatic cancer treatment.